During the past decade the new revelations that vitamin D must be metabolized before it is biologically active have revolutionalized concepts regarding the role of vitamin D in disorders of calcium metabolism. The rebirth in vitamin D research has spawned a renewed interest in developing analogs of vitamin D that have selective 1Alpha,25-(OH)2-D-agonist or antagonist properties. Such compounds could be invaluable in the treatment of hypo- and hypercalcemic disorders related to acquired or heritable disorders of vitamin D metabolism. (1) We are interested in making water-soluble derivatives of vitamin D and its metabolites. The method which we have initiated to achieve this solubility is to chemically bond glycosides to the fat-soluble vitamin. Such compounds may have wide utility for intravenous vitamin D administration and for treatment and prevention of vitamin D deficiency in patients with intestinal fat malabsorption syndromes. (2) We want to analyze how small changes in the stereochemistry of the A-ring of 1Alpha,25-(OH)2-D3 influence its (a) target tissueuptake, (b) organelle distribution, (c) effect on regulating the renal 25-OH-D-1Alpha-hydroxylase activity, and (d) biological activity. We have synthesized the following compounds to use in these studies: 1Beta,25(OH)2-D3, [1Alpha-3H]1Beta,25-(OH)2-D3, [1Beta-3H]1Alpha,25-(OH)2-D3, 1Alpha,25-(OH)2-3-epiD3, and 3-epivitamin D3. Results from such investigations should provide insights into developing analogues of vitamin D with (a) selective target organ activity (e.g., intestine vs. bone), (b) antagonistic activity to block the biological action of 1Alpha,25-(OH)2-D3 in disease states where there is an over-production of 1Alpha,25(OH)2-D3, and (c) agonistic activity to feed-back regulate the renal 25-OH-D-1Alpha-hydroxylase as another mechanism to treat patients who overproduce this hormone. (3) We will also synthesize a photolabile derivative of 1Alpha,25-(OH)2-D3 that will be used as a photoaffinity label for the cytosolic 1,25-(OH)2-D receptor.